Recombinant human <scp>C1</scp> esterase inhibitor as prophylactic treatment in idiopathic non‐histaminergic angioedema
Authors: Mehran Alizadeh Aghdam, Zonne L. M. Hofman, Michelle Meertens, Ans Lebens, C. Erik Hack, André C. Knulst, Coen Maas, Heike Röckmann
Journal: Allergy (2022)

Idiopathic angioedema is characterized by cutaneous and mucosal swellings in the absence of diagnostic laboratory parameters and family anamnesis.1 Patients who do not respond to prophylactic antihistamine therapy are diagnosed as idiopathic non-histaminergic AE (InH-AAE) according to the definition of the Hereditary Angioedema International Working Group.2 Recombinant human C1 esterase inhibitor ([rhC1-INH], Conestat alfa/Ruconest®) is an effective and safe treatment for acute attacks and prophylaxis of angioedema (AE) in hereditary angioedema (HAE) type 1 and 2.3 Given the unresponsiveness to antihistamines in part of Inh-AAE patients, indicating possible involvement of the bradykinin route, we investigated the effectiveness and safety of rhC1-INH prophylaxis in InH-AAE. In this phase 2, explorative, prospective, single-centre, open-label study, six patients with InH-AAE were enrolled (Table 1)(ethics approval number 17–139). A four-week observation period was followed by an eight-week treatment period with rhC1-INH (twice weekly 50 IU/kg; max 4200 IU), and another four-week observation period (Figure 1; see also supplemental for detailed information about inclusion criteria, study design and funding source). In patient 1, attack frequency was reduced by 85% (6.7-fold) (3 versus 20 attacks, respectively; Figure 1). Angioedema activity scores over 28 days4 (AAS28) decreased 8-fold with an accumulated AAS score of 29 in the two treatment months versus 233 in the two observational months. Of patients 2 to 6, none showed a clinical response to rhC1-INH. rhC1-INH treatment did not lead to adverse events, or thrombotic events. The percentage of cleaved high molecular weight kininogen (%cHK), C1-esterase inhibitor (C1-INH), high molecular weight kininogen (HK), plasma kallikrein (PK) and factor XII (FXII) (see Figures S1, S2 and supplemental for method) did not differ between treatment and observation period and were not indicative of treatment response. Mean D-dimer, C-reactive protein (CRP) and leukocyte counts in patients were within, or slightly above normal. None of the patients had an AE attack during blood sampling. Genetic analysis in patient 1 supported the diagnosis InH-AAE, since no known gene mutations associated with HAE were identified (Table S1). Patient 1 31 y/oFemale ER visit 1× Adrenalin i.m. 0.3 mg 4× bPrednisone 0.5 mg/kg 3× AH 1dd 1-2× rhC1-INH (1000 IE 2/w) pdC1-INH (4200 IE 2/w) Prednisolone Omalizumab (300 mg/4 w) TA (1000 mg 3 d) Patient 2 37 y/o Female ER visit 1× Adrenalin 1× bPrednisone 0.5 mg/kg 6× AH 1-2dd 8× Patient 3 56 y/o Male Patient 4 33 y/o Male TA (500 mg 3 d) AH (5 mg 1 d) Patient 5 25 y/o Female Omalizumab (300 mg/4 w) Icatibant (attack treatment) Patient 6 60 y/o Female Omalizumab (300 mg/4 w) Post-trial, patient 1 restarted rhC1-INH treatment achieving again rapid and complete remission for 6 months, even being able to extend the treatment interval to 5 days. Due to health insurance limitations, treatment was switched to omalizumab 300 mg/4 weeks and tranexamic acid 1000 mg twice daily for 3 months, resulting in recurrence of frequent and severe attacks. Restarting treatment with 1000 IU plasma derived C1-INH (pdC1-INH) every 3–4 days for 1 year led to immediate and complete symptom control. After 1 year, treatment was switched to 4200 IE rhC1-INH since herewith, remission could be achieved with longer intervals of 5–6 days. Similar response to pdC1-INH and rhC1-INH, but not to omalizumab, made a placebo response unlikely. Patients 2, 5 and 6 (rhC1-INH non-responders) also initiated omalizumab treatment, with good/near complete response in patients 2 and 6, respectively, and no effect in patient 5 (Table 1). Patient 5 also showed no response to icatibant attack treatment. This first prospective trial showed successful rhC1-INH treatment in one out of six patients with InH-AAE. Three previous case reports described effectiveness of plasma derived (p)dC1-INH prophylaxis in four patients with InH-AAE.5-7 Our data show that only a proportion of patients may respond to C1-INH treatment. Failure of rhC1-INH in the other 5 InH-AAE patients may suggest that bradykinin is not involved or a dose of 50 IU rhC1-INH per kg was too low. None of the measured biomarkers of the bradykinin route was indicative for the observed effect in the responding patient. However, recent studies showed that in InH-AAE the clinical picture might be caused by different and in part unknown genetic defects, leading to impairment of different factors of the contact system and resulting in a reduced control of the kallikrein system and alteration of bradykinin as main mediator.8, 9 Levels of bradykinin might provide a better biomarker for such activation, however, obtaining reliable samples during an attack is complex. According to the current guidelines, omalizumab is the first choice of treatment for patients with idiopathic angioedema not responding to high dose antihistamins.10 Response to omalizumab may support mast cell driven disease mechanisms in patients 2 and 6. However, bradykinin cannot completely be ruled out as the main mediator of AE even in conditions commonly associated with mast cell activation, for example in anaphylaxis.11 This study was limited by its monocentric design and the small sample size. In conclusion, rhC1-INH treatment was effective in 1 of the 6 InH-AAE patients, and omalizumab in 2 out of 4 suggesting a heterogeneous pathogenesis of AE and, consequently, the need for personalized treatment. This study is financed in part by Pharming Group N.V. We would like to thank the patients, and Dutch AE patient organization for their participation in support of this study. We thank Simone Smits, Stans den Hartog Jager, Henny Otten, Mignon van den Elzen and Paco Welsing for their contributions and thoughts regarding the laboratory analysis and methodology setup. We thank Luca Bellizzi, Tobias Suiter, Elly Sakiman and Pharming Technologies for their support and insight. Mehran Alizadeh Aghdam received speakers fee from Novartis to institution. Zonne Hofman received contribution to publication cost thesis from Pharming Technologies. André Knulst is a member of advisory board, Novartis. Health care innovation grant from Novartis to institution. Coen Maas has been advisor to Shire/Takeda and Biomarin. Heike Röckmann is a member of national advisory board Novartis, Sanofi. Michelle Meertens: None. Erik Hack: None. Ans Lebens: None. Appendix S1 Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.